In viviparous species, the conceptus must be protected from a potentially hostile maternal immune system. The major histocompatibility complex (MHC) is a genetic region that encodes MHC class I and class II proteins, which present peptide antigens to T lymphocytes and induce graft rejection. The MHC, class II proteins are only expressed on professional, antigen-presenting cells. However, classical, MHC class I proteins are expressed on all nucleated somatic cells. Protection of the conceptus from immune-mediated rejection involves downregulation of classical MHC class I antigen expression on trophoblast cells, which form the external epithelial layer of the placenta, and maintenance of an immunologically favorable immunosuppressive environment in the uterus. Normally, bovine trophoblast cells do not express MHC class I antigens before d 120 of pregnancy. However, during the last third of gestation, trophoblast cells in the inter-placentomal and arcade regions of the placenta express classical, MHC class I proteins, which could potentially induce fetal rejection, as well as nonclassical, MHC class I proteins. A human, nonclassical, MHC class I antigen, human leukocyte antigen G, is an important immunoregulatory factor required for the maintenance of pregnancy. In cattle, MHC class I expression during the last third of pregnancy has no adverse effects and probably contributes to placental separation at parturition. However, somatic cell nuclear transfer (SCNT) conceptuses, the majority of which are aborted between d 30 and 90 of pregnancy, had trophoblast cell expression of MHC class I antigens before d 34 of pregnancy. In conjunction with increased trophoblast MHC class I expression, SCNT pregnancies exhibited a marked increase in the number of stromal lymphocytes in the uteri of surrogate dams. A retrospective study found that SCNT pregnancies established using MHC class I-homozygous cell lines, in which the immunological barrier is greatly reduced, had significantly improved fetal survival from d 28 to term (51% survival for MHC-homozygous and 5% for MHC-heterozygous SCNT fetuses). Consequently, it appears that the high rate of fetal mortality in SCNT pregnancies is due, at least in part, to inappropriate expression of trophoblast, MHC class I antigens resulting in immune-mediated placental rejection. This suggests that appropriate regulation of MHC class I genes is critical for immunological acceptance of an allogeneic conceptus.